Heparin, a sulfate-containing polysaccharide, is widely used clinically as a parenterally administered agent for the treatment and prevention of thrombosis. However, a very significant problem at heparin therapy is that the half life of heparin in blood is short, or about 1.5 hours. Because of this, heparin must ordinarily be administered by continuous intravenous infusion or by subcutaneous injection two to three times per 24 hours.
Presence of the plasma protein antithrombin III is a necessary prerequisite for the anticoagulation activity of heparin. Antithrompin III inhibits most of the coagulation enzymes which are formed at the blood coagulation. But these inhibition reactions are slow and insufficient to prevent blood from coagulating. When heparin is present, it is bound to antithrombin III and activates said antithrombin III to form an inhibitor with a greatly increased reactivity which is sufficient to prevent the coagulation. The heparin-antithrombin bound in this inhibitor is not covalent bound but is reversible.
Collen et al, Abstracts VIII Int. Congr. Thromb. Haemostasis, Thrombos. Haemostas. 46, 185 (1981), describe a product obtained by covalent coupling of standard heparin to antithrombin III. The products obtained had the properties of rapidly inhibiting the coagulation enzymes thrombin and activated Factor X. The products were shown in tests on rabbits to have a half life in blood which was two to three times longer than the half life of standard heparin. However, even though this represents a step forward, there is a need for heparin products with longer half life in blood and accordingly with longer duration of therapeutic activity. The present invention provides such heparin products with a very long half life in blood and correspondingly long duration of anticoagulation activity.